KVD900, a new oral on-demand treatment of hereditary angioedema attacks achieves complete plasma kallikrein suppression: safety, tolerability, pharmaco-

kinetic and pharmacodynamic results from a phase 1 first-in-human study

Andreas Maetzel, Michael Smith, Edward Duckworth, Sally Hampton, Gian Marco De Donatis, NivethaMurugesan, Louise Rushbrooke, Lily Li, Danielle Francombe, Edward Feener and Chris Yea

Saturday May 25, 2019 O-25 11:00 – 12:30

• HAE attacks are unpredictable in frequency and severity1

• Immediate access to on-demand treatment for HAE attacks is mandatory2

• Early initiation of on-demand treatment significantly shortens attack duration3,4

• A rapid oral, on-demand treatment may stop attacks early at onset, addressing a significant worldwide need of HAE patients

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______Source: (1) Bork K. et al., J Allergy Clin Immunol 2012;130:692-7 PMID: 22841766; (2) Maurer M et al. Allergy. 2018 Aug;73(8):1575-1596. doi: 10.1111/all.13384. Epub 2018 Mar 12. PMID: 29318628; (3) Craig TJ et al. Ann Allergy Asthma Immunol 111 (2013) 211e215; (4) Maurer M et al. PLoS ONE 8(2): e53773. doi:10.1371/journal.pone.0053773

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Intercritical Mature attack

Swelling / Pain

Early

Attack onset

Prophylaxis “Classical” acute Rx.Prodromal

Intervene early during PKa activation

Early inhibition of plasma kallikrein activation may pre-empt swelling and pain

Evaluate single doses of KVD900 (powder in capsule & tablet):

• ..safety and tolerability

• ..pharmacokinetics (PK)

• ..pharmacodynamics (PD)

• ..exposure fasted vs. fed

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• Phase 1 study in healthy, adult male volunteers (18y to 55y) in three parts:

– Part A: single ascending dose, capsules, 5 mg to 600 mg, random: n=6 active, 2 placebo, empty stomach

– Part B: single dose capsule vs. tablet x-over, 100 mg, n=8, empty stomach

– Part C: single dose tablet, empty stomach vs full meal, x-over, 600 mg, n=12

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6

Healthy subjects, male, > 18y, randomized to active & placebo

Single-dose: fasted vs. fed n=12

Placebo10mg

Placebo20mg

Placebo80mg

Placebo40mg

Placebo160mg

Placebo300mg

600mg

Placebo5mg

Single-dose (caps): Safety, PK & PD n=6 & 2 × 8

Tablet100mg

Capsule100mg

Capsule100mg

Tablet100mg

wash-out

Single-dose: capsule vs. tablet

n= 8

Fasted600mg

Fed600mg

Fed600mg

Fasted600mg

wash-outPlacebo

• Tandem MS-MS for KVD900 concentrations

• Dextran sulfate (DXS) stimulation:

– fluorogenic enzyme assay (whole plasma)

– capillary-based high molecular weight kininogen (HK) cleavage immunoassay (whole plasma)

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8

Factor XIIa

Factor XII

Stimulus Plasma Prekallikrein

Plasma Kallikrein

High Molecular Weight Kininogen

• Increased vascular permeability

• Pro-inflammatory

• Vaso-active

Brady-Kinin

CleavedHK

KVD900

PKa Enzyme Assay

HK Cleavage Assay

Both tests measure the activity of plasma kallikrein in cleaving target substrates

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• No SAEs reported

• 25/26 AEs were mild

– One moderate (headache at 10mg)

– No GI AEs considered related to KVD900

• No subjects withdrawn

• No clinically significant changes in vital signs, ECG, safety labs

Cohort N AEs Verbatim Reported Symptom

5mg 6 2 Back pain, dizziness (possibly related)

10mg 6 1 Headache (moderate)

20mg 6 1 Nasopharyngitis

40mg 6 - -

80mg 6 1 Cough

160mg 6 3 URTI, myalgia, nasopharyngitis

300mg 6 - -

600mg 6 - -

100mg (bridge) 8 - -

600mg (fasted vs. fed)

12 15 5 x headache (1 possibly, 3 probably related)3 x fatigue (2 possibly related)2 x lethargy (probably related)1 x each: vomiting, folliculitis, eczema, arthropod bite, presyncope

Placebo 16 3 Back pain, oral herpes, oropharyngeal pain

Administration of single doses of KVD900 up to 600 mg is generally safe & well tolerated

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KVD900 rapidly achieves maximal plasma exposure

The KVD900 tablet formulation further exceeds the fast absorption seen with the capsule

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IC50

KVD900 concentrations rapidly exceed multiples of IC50 within 20 minutes irrespective of food intake

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KVD900 achieves instantaneous PKa enzyme inhibition and maintains near complete suppression of activity for 8 hrs

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~ 2,000 IU C1INH

The level of HK protection afforded by C1INH is sustained for 10hrs

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DXS @ 17’ pre-dose 1hr 6 hrs 8 hrs 10 hrs 12 hrsNo DXS

Subj. 2

Subj. 3

Subj. 4

Subj. 5

Subj. 6

Subj. 1

Ph. 1 subjectsControls

HK cleavage protection is upheld for up to 12 hrs

• First-in-human study of KVD900 in 68 subjects

• Single oral administration of up to 600 mg KVD900 is generally safe and well tolerated without any severe adverse events and no related GI events

• KVD900 achieves rapid suppression of plasma kallikrein activity

• KVD900 achieves sustained protection of intact HK

• KVD900 concentrations rapidly exceed multiples of IC50 within 20 minutes irrespective of food intake

• Phase 2 study currently ongoing to evaluate potential of KVD900 for on-demand suppression of HAE attacks

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